Cancer cells exhibit altered metabolism, characterized by increased glucose uptake and increased glycolysis under aerobic condition, a process known as Warburg effect. The exact molecular mechanisms underlying cancers dependency on altered metabolic pathways remains unclear. Our long-term goal is to elucidate how metabolic reprogramming in cancer cells regulates growth and survival pathways and to exploit these pathways for therapeutic gain. Regulation of proteins by O-GlcNAc modifications is a reversible process that depends on glucose availability and is a powerful mechanism to regulate protein function. In this proposal, we will elucidate the mechanisms of how the nutrient sensor O-GlcNAc transferase (OGT), enzyme responsible for catalyzing addition of O-GlcNAc to proteins, regulates cancer growth and survival. In Aim #1, we will determine how alterations in O-GlcNAc regulate the oncogenic transcription factor FoxM1. This aim will elucidate the precise molecular mechanisms of how OGT targets FoxM1 for degradation via regulation of APC/C-Cdh1 and how this pathway effect growth control in cancer cells. In Aim #2, we will investigate how OGT regulation of FoxM1 provides cell survival signals to cancer cells. We will determine whether alterations in O-GlcNAc causes FoxM1-dependent alterations of ROS levels leading to p53-dependent apoptosis of cancer cells. In addition, we will begin to identify apoptotic factors regulated by OGT/FoxM1 pathway. The final aim will characterize and test whether novel OGT inhibitors can block cancer cell phenotypes in vitro and in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to cell growth and survival pathways and identify novel anticancer agents. PUBLIC HEALTH RELEVANCE: This grant will help elucidate molecular pathways altered in cancer. Specifically, we will focus on how metabolic reprogramming in breast cancer cells regulates growth and survival pathways. Additionally, we will test novel agents for their anti-tumor properties thus this proposal may help establish a new therapeutic target for treatment of cancer.